Hypertension & CV Adverse Events With Ibrutinib in 'Real World'

Alexander M. Castellino, PhD

October 08, 2019

Since its approval in 2016, ibrutinib (Imbruvica, Pharmacyclics) has rapidly changed the treatment landscape of chronic lymphocytic leukemia (CLL) and several rarer hematologic malignancies. However, emerging real-world data are now suggesting caution, owing to increased risk for hypertension and other cardiovascular adverse events.

A study published online October 3 in Blood reported a retrospective analysis of data from the real-world setting. The study found that 3 of 4 patients who used ibrutinib developed new or experienced worsened hypertension over 30 months and that new hypertension was reported in 71.6% of ibrutinib users.

"Our study highlights that prevalence of hypertension among ibrutinib users was higher than previously thought and that patients who develop hypertension have the potential to develop other cardiac events," lead author Daniel Addison, MD, co-director of cardio-oncology at Ohio State University's Comprehensive Cancer Center, told Medscape Medical News.

"Hypertension is beginning to emerge as a significant adverse event among patients on ibrutinib and was not previously well described in the ibrutinib label," Addison said. He added that other cardiovascular events described in their article also occur at a higher frequency than initially described in ibrutinib's clinical trials.

Hypertension is beginning to emerge as a significant adverse event among patients on ibrutinib. Dr Daniel Addison

"It is important to emphasize that ibrutinib is a lifesaving therapy with dramatic cancer treatment benefits, including improved survival; it has become ubiquitous to the treatment of many blood cancers and will continue to be applied to other cancers," Addison said in a statement released by the American Society of Hematology. "Accordingly, we need to find the best ways to manage high blood pressure and protect against other heart-related issues," he added.

Addison and his colleagues embarked on this analysis following increasingly frequent observations of cases of new and resistant hypertension among cancer patients who were taking ibrutinib, as well as reports from other researchers of a higher incidence of atrial fibrillation, ventricular arrhythmias, and sudden cardiac death.

One of these reports, which was published October 1 in the Journal of the American College of Cardiology (JACC), used the World Health Organization's pharmacovigilance database (WHO VigiBase) to analyze adverse events associated with ibrutinib. The researchers found that sudden death was reported for 303 ibrutinib users in the real world. Those deaths were linked to seven cardiovascular (CV)-related events: supraventricular arrhythmias, central nervous system (CNS) hemorrhagic events, ventricular arrhythmias, heart failure, conduction disorders, CNS ischemic events, and hypertension.

"Clinical trials often do not reflect the real-world population, which often has a higher prevalence of cardiovascular diseases and risk factors," a corresponding author of that study, Javid J. Moslehi, MD, of the Vanderbilt University Medical Center, Nashville, Tennessee, told Medscape Medical News.

These analyses were not performed on a whim, Moslehi noted. He said that they were undertaken after the presentation of the ALLIANCE A41202 study at the 2018 annual meeting of the American Society of Hematology, which was reported at the time by Medscape Medical News.

"Although patients on any of the ibrutinib arms of the study had better cancer outcomes compared with those receiving chemotherapy, the incidence of sudden death was higher in any of the ibrutinib arms of the study: 7% sudden death if you were on ibrutinib compared to 1% if on chemotherapy," Moslehi told Medscape Medical News.

This raised a red flag. "Patients don't suddenly die.... We wanted to know the cause of death in these patients," Moslehi said.

In the prescribing information (PI) for ibrutinib, the rate of these events is indicated as being much lower. According to the PI, among 1124 patients who were treated with the drug in clinical trials, the rate of hypertension of any grade was 12%; for hypertension of grade 3 or higher, it was 5%. The PI calls for monitoring blood pressure when therapy is initiated and recommends initiating or adjusting antihypertensive therapy throughout treatment.

Additionally, the PI indicates that fatal and serious cardiac arrhythmias have occurred in clinical studies: it lists ventricular tachyarrhythmias of grade 3 or greater as occurring in 0.2% of patients, and atrial fibrillation and atrial flutter of grade 3 or greater as occurring in 4% of patients.

These rates, which are reported from clinical trials, underrepresent the frequency of these events in the real world, suggests Jutta Bergler-Klein, MD, from the Department of Cardiology at the Medical University of Vienna, Austria, in an editorial that accompanies the article in JACC.

"The net benefit of ibrutinib may be offset by sequential cardiovascular mortality, which will presumably rise further with continuous therapy required to tackle residual disease or relapse," she cautions.

The CV adverse events associated with ibrutinib that were reported in these studies have been noted at other treatment centers too. Joerg Herrmann, MD, director of cardio-oncology at the Mayo Clinic in Rochester, Minnesota, said that all the cardiac adverse events reported in these studies have been seen in their patients: "Yes, we have seen this at Mayo, and they [ie, the authors of the study] beat us to it," he said.

Cardiologist Brian C. Jensen, MD, of the UNC McAllister Heart Institute, Chapel Hill, North Carolina, told Medscape Medical News that ibrutinib-induced hypertension has been observed in their cardio-oncology clinic. "However, the most common reason for referral of patients taking ibrutinib is atrial fibrillation," he said.

He also commented that the oncologists at his center are well aware of the association between ibrutinib and arrhythmias, particularly atrial fibrillation.

"As a cardiologist and a scientist, I think it is fascinating that ibrutinib is associated with arrhythmias, given that there is no previously recognized role for its molecular target (Bruton tyrosine kinase) in the heart," he said.

Jensen also noted that, especially for patients with CLL, ibrutinib remains among the first-line agents. "I don't know that oncologists routinely factor cardiovascular comorbidities in their choice of agents," he commented.

"A history of CV disease does not preclude the use of ibrutinib, given its therapeutic efficacy," Jensen said. However, the findings from the Blood article suggest that it might be reasonable to consider other agents for patients with CLL who have a history of refractory hypertension.

Details of the Real-World Hypertension Findings

The real-world study of the occurrence of hypertension in patients taking ibrutinib reported by Addison and colleagues involved a retrospective review of 562 patients consecutively treated with ibrutinib at Ohio State University's Comprehensive Cancer Center.

Most of these patients (70.6%) were men (mean age, 63.8 years). Many of them (62%) already had a history of hypertension, and 63% were taking at least one antihypertensive medication.

Most of these patients (73.9%) were taking ibrutinib for CLL; the drug was used in combination with other agents in 30.8% of patients.

After a median follow-up of 30 months, new or worsening hypertension (systolic blood pressure [SBP] >103 mmHg) was reported in 78.3% of patients; in 84.8% of these patients, ibrutinib was considered to be the probable cause.

Among patients who did not have hypertension at baseline, new hypertension was reported in 71.6%; the mean increase in SBP was 13.4 mmHg.

Hypertension of grade 3 or 4 was observed in 37.6% of patients; 17.7% of these patients did not have hypertension at baseline.

At 4.2 months after initiating ibrutinib treatment, the cumulative incidence of hypertension was 50%.

Antihypertensive medication was initiated or another agent was added for 37.2% of patients taking ibrutinib; 18% of ibrutinib users experienced resistant hypertension and required the use of three or more antihypertensive agents.

Major adverse cardiovascular events (MACE) were observed in 16.5% of patients; most were attributed to ibrutinib. New or worsening hypertension was associated with increased risk for MACE (hazard ratio [HR]: 2.17; 95% confidence interval [CI]: 1.08 – 4.38) and atrial fibrillation or ventricular arrhythmias (HR: 3.18; 95% CI: 1.37 – 7.37).

In these patients, initiation of antihypertensive medication reduced the risk for MACE (HR: 0.40; 95% CI: 0.24 – 0.66).

However, Addison and colleagues reported that in an analysis of patients who were progression free and who had been taking ibrutinib for longer than 1 year, new or worsening hypertension was not associated with increased mortality or progression.

Details of the WHO VigiBase Study

The other recently reported study involved a case/noncase, or disproportionality, analysis based on adverse drug reactions (ADRs) reported in VigiBase.

Using the disproportionality analysis, the reserchers were able to determine whether suspected drug-induced CV events were differentially reported with ibrutinib compared with CV events reported in the entire database, Moslehi and colleagues explain.

In this disproportionality analysis, specific ADRs reported for ibrutinib were compared with the proportion of the same ADRs in the entire database.

Individual case safety reports were available for 13,572 patients taking ibrutinib vs 8,318,890 patients in the entire database. Patients taking ibrutinib were at a significantly higher risk for the following:

  • Supraventricular arrhythmias (odds ratio [OR]: 23.1; P < .0001)

  • CNS hemorrhagic events (OR: 3.7; P < .0001)

  • Heart failure (OR: 3.5; P < .0001)

  • Ventricular arrhythmias (OR: 4.7; P < .0001)

  • Conduction disorders (OR: 3.5; P < .0001)

  • CNS ischemic events (OR: 2.2; P < .0001)

  • Hypertension (OR: 1.7; P < .0001)

Moslehi indicated that heart failure and conduction disorders emerged from these analyses as two new safety signals and that these events occurred early after ibrutinib administration.

Heart failure associated with ibrutinib had been previously described in case reports. Many of the heart failures seen in the study were not due to an underlying cause, which suggested that they were related to the drug.

Moslehi pointed out that conduction disorders, seen for the first time with ibrutinib in this analysis, are associated with high mortality. Indeed, fatalities ranged from 10% for supraventricular and ventricular arrhythmias to 20% for CNS events, heart failure, and conduction disorders.

"Disproportionality analysis in pharmacovigilance databases is an important method to detect signals in drug safety research and post-marketing surveillance," Moslehi and his colleagues note in their discussion of the study.

Lessons for Clinical Practice

Both Addison and Moslehi agree that ibrutinib has dramatically changed the treatment of CLL and some other hematologic malignancies, but they feel that these new observations require that patients who receive ibrutinib be monitored more closely.

Ibrutinib is an oral medication, so many patients who take the drug do not frequently see their oncologist. "Patients typically see their oncologists in the clinic according to the nature of their cancer, but remaining vigilant for cardiovascular disease should be a high priority," Addison said.

"Hypertension is not typically reported in clinical trials until it reaches grade 3 [SBP/diastolic blood pressure: 160/100 mmHg]," Addison said. "The message for physicians is, monitor blood pressure more closely and treat hypertension when it develops to help prevent other cardiac events," he added.

He indicated that patients who take ibrutinib should decide with their physicians the most appropriate way to monitor the course of blood pressure, including the use of home monitoring.

Jensen indicated that ibrutinib-induced hypertension can be managed using standard approaches, although some data suggest that calcium channel blockers are most effective in managing hypertension associated with other kinase inhibitors.

"No specific drug clearly protected against hypertension," Addison said, and no particular class is more effective than another. He is optimistic that their new study, along with others that are presented at meetings, will increase awareness that these adverse events occur more frequently in the real world than in clinical studies.

"Managing ibrutinib-induced atrial fibrillation can be more challenging," Jensen said. He pointed out that ibrutinib is associated with an increased risk for major bleeding, which can complicate decision making with respect to therapeutic anticoagulation.

"In patients with low stroke risk (CHA2DS2-VASc score of 0 or 1), it is reasonable to continue ibrutinib," he said, but in patients at higher risk, it is not uncommon to seek alternatives to ibrutinib. "Adding anticoagulation increases bleeding risk unacceptably, and continuing ibrutinib without anticoagulation increases stroke risk," Jensen said.

Moslehi told Medscape Medical News that in the age of personalized medicine, it is important to identify which patients may benefit from ibrutinib, but also which patients may be harmed. "We need to understand the mechanism behind why ibrutinib is causing these events in some patients," he said.

"Predictors of MACE, including arrhythmias, during ibrutinib use are not well understood," Addison and colleagues write. "Data from prior studies and smaller prospective investigations have suggested that traditional factors including age, prior atrial fibrillation, diabetes, myocardial infarction, and heart failure may underlie some of the observed risk," they add.

"These events can potentially be managed," Addison told Medscape Medical News. He added that, moving forward, more collaboration is required between oncologists and cardiologists. Indeed, cardio-oncology is emerging as a new discipline in hospitals and academic institutions. Both Addison and Moslehi are co-chairs of cardio-oncology divisions at their respective institutions.

"Cardio-oncology is an unmet need in cancer patients," Addison said. "Heart problems are a main driver of survivorship issues among cancer patients," he told Medscape Medical News.

Medscape Medical News contacted Pharmacyclics, the makers of ibrutinib, for comment but had received no response at the time of publication.

Moslehi has served on advisory boards for Pharmacyclics, Bristol-Myers Squibb, Pfizer, Novartis, Regeneron, Takeda, Deciphera, and Myokardia and has received research funding from Pfizer and Bristol-Myers Squibb. No other relevant financial relationships have been disclosed.

Blood. Published online October 3, 2019. Abstract

J Am Coll Cardiol. Published online October 1, 2019. Abstract, Editorial

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